title: A novel adamantyl benzylbenzamide derivative, AP736, suppresses melanogenesis through the inhibition of cAMP-PKA-CREB-activated microphthalmia-associated transcription factor and tyrosinase expression.
abstract: Melanogenesis is essential for the protection of skin against UV, but excessive production of melanin causes unaesthetic hyperpigmentation. Much effort is being made to develop effective depigmenting agents. Here, we found that a tyrosinase inhibitor, AP736 (5-adamantan-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzamide) potently suppresses tyrosinase expression, and the mechanism underlying was elucidated. AP736 attenuated the melanin production induced by diverse melanogenic stimuli in murine and human melanocytes. It suppressed the expression of key melanogenic enzymes; tyrosinase, tyrosinase-related protein-1 and tyrosinase-related protein-2. The expression of microphthalmia-associated transcription factor (MiTF), a major promoter of melanogenesis was also decreased. AP736 inhibited the activation of cAMP response element-binding protein (CREB) and phosphokinase A (PKA), and cAMP elevation, reflecting that cAMP-PKA-CREB signalling axis was suppressed, resulting in the downregulation of MiTF and tyrosinase. Along with the previously reported tyrosinase inhibitory activity, the suppression of cAMP-PKA-CREB-mediated MiTF and tyrosinase expression by AP736 may be efficient for the treatment for hyperpigmentation.
authors.affiliation: Amorepacific CO R&D Center, Yongin-si, Korea.
authors.forename: Chang Seok
authors.initials: CS
authors.lastname: Lee
authors.forename: Won-Hee
authors.initials: WH
authors.lastname: Jang
authors.forename: Miyoung
authors.initials: M
authors.lastname: Park
authors.forename: Kyoungmi
authors.initials: K
authors.lastname: Jung
authors.forename: Heung Soo
authors.initials: HS
authors.lastname: Baek
authors.forename: Yung Hyup
authors.initials: YH
authors.lastname: Joo
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Park
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D001549:Benzamides / Q000737:chemistry*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D017495:Hyperpigmentation / Q000378:metabolism; D008543:Melanins / Q000737:chemistry; D008544:Melanocytes / Q000166:cytology; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000037:antagonists & inhibitors*; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism
chemical_list: C000592311:5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxybenzamide; D001549:Benzamides; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases; D000218:Adamantane
keywords: cAMP response element-binding protein; melanocyte; melanogenesis; microphthalmia-associated transcription factor; tyrosinase